The objective of this Phase II STTR grant application is to continue the R/R&D efforts initiated in Phase I. The long-term objective for Arrhythmotech is to develop and market an instrument for the simultaneous recording of sympathetic nerve activity (SNA) and electrocardiogram (ECG) using electrodes on the skin. This method (neuECG) was discovered in Dr. Chen's research laboratory at the Krannert Institute of Cardiology, and a patent application has been filed by Indiana University. Arrhythmotech LLC was founded to further advance this concept, and we propose that neuECG will have significant commercial value by providing a new tool for arrhythmia prediction and detection. Significant progress has been made with the Phase I STTR funding. Phase II will expand the clinical research to firmly validate the neuECG as a method to estimate cardiac sympathetic tone, and to develop and test prototypes that can be used for future clinical investigations, while laying th groundwork for Phase III commercialization of the first application. Sympathetic tone is important in cardiac arrhythmogenesis. However, the existing method of SNA measurement is either invasive or not accurate. We have therefore developed methods to directly record SNA from either subcutaneous tissues or on the surface of the skin in canine models. We found that both subcutaneous nerve activity (SCNA) and superficial skin sympathetic nerve activity (SKNA) closely correlate with stellate ganglia nerve activity (SGNA) in ambulatory dogs. With the generous support of a Phase I STTR grant, we were able to obtain preliminary results in human patients that strongly suggest the validity of SKNA in estimating sympathetic tone. We have successfully developed prototypes that can be used for long-term SKNA recording. We will pursue the following Specific Aims. Specific Aim 1: Unequivocally validate SKNA as a highly accurate non-invasive measure of skin SNA with simultaneous microelectrode recordings. These studies will be performed by Dr. Ronald Victor of Cedars-Sinai Medical Center. Specific Aim 2: To test the hypothesis that lidocaine injection into the stellate ganglion or surgical stellectomy will reduce or eliminate the SKNA recorded from the arms. These studies will be done by Dr. Yong-Mei Cha of the Mayo Clinic. In addition to validating SKNA as a measure of skin SNA, these studies may also lead to commercial applications by providing a tool to measure the success of neuromodulation procedures. Specific Aim 3: Demonstrate that SKNA as measured by neuECG can serve as a novel biomarker for testing atrial fibrillation vulnerability. These studies will be done at Indiana University. Our preliminary results indicate that specific SKNA patterns are closely associated with the spontaneous occurrence of paroxysmal AF. Those specific patterns can be considered as novel biomarkers that are useful in arrhythmia management, such as guiding radiofrequency catheter ablation procedures and predict the long term success of these procedures. Successful completion of these 3 specific aims will give Arrhythmotech, LLC an excellent platform for future commercial applications.